Approximately 85% of individuals with Mucopolysaccharidosis (MPS) type I, II, or VI report weekly pain and 50-60% have significant limitations in their activities of daily living due to MPS related musculoskeletal disease despite treatment with enzyme replacement therapy (ERT). Thus there is a critical need to identify additional therapies to alleviate the burden of musculoskeletal disease in order to improve the health and quality of life of individuals with MPS. However, disease progression needs to be quantified to be able to determine efficacy of new therpies. The proposed study is a multi-institutional, 5-year, longitudinal study of musculoskeletal disease in MPS. The long-term goal is to identify and test new therapies for musculoskeletal disease in MPS. The objective of this proposed study is to quantitatively describe the progression of skeletal disease and identify biomarkers that either predict disease severity or could be used as therapeutic targets in individuals with MPS I, II, and VI. Our central hypothesis is that skeletal disease will progress over time and that biomarkers of inflammation, and bone and cartilage turnover, will predict the severity of skeletal disease over time. Specific aims are 1) to characterize the progression of skeletal disease from childhood into young adulthood and 2) to identify prognostic biomarkers of inflammation, bone remodeling, and cartilage turnover that can predict the progression of skeletal disease and impaired physical function. To achieve these aims, participants will be evaluated annually with measures of bone health (dualenery x-ray absorptiometry, peripheral quantitative computer tomography, hip and spine x-rays), physical function (muscle strength by Biodex and hand grip dynamometer, range of motion testing, and questionnaires of physical function and pain), and laboratory measurements of biomarkers of bone turnover, cartilage breakdown, and inflammation. A database of standardized measurements of musculoskeletal disease in MPS will allow the field to efficiently move forward with therapeutic clinical trials in patients with MPS.